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      Efficacy and toxicity of cladribine for the treatment of refractory acute myeloid leukemia: a meta-analysis

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          Purpose: To investigate the overall efficacy and toxicity of cladribine and cladribine-based chemotherapy in the treatment of patients with refractory acute myeloid leukemia (AML) based on meta-analysis.

          Methods: PubMed, EMBASE database, and the Cochrane Library were searched for relevant studies. Eligible studies were clinical trials of refractory AML assigned to cladribine with data on efficacy including complete remission (CR) rate, overall response rate (ORR) and overall survival. Toxicity was evaluated based on the early death rate and the incidence of grade 3 and 4 adverse events (AEs).

          Results: A total of 10 clinical trials including 422 refractory AML patients were analyzed. The overall CR rate was 42.2% (95% CI: 31.0–54.3%). And the ORR of seven trials including 235 patients was 49.7% (95% CI: 33.5–66.0%). The overall early death rate of 260 patients enrolled in five trials was 6.8% (95% CI: 4.3–10.6%). Thrombocytopenia, anemia, neutropenia, and infection were the most common grade 3 and 4 AEs.

          Conclusion: Cladribine is effective for refractory AML, and its efficacy can be increased with the combination of cladribine, cytarabine, and granulocyte-colony stimulating factor regimen.

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          Most cited references 31

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          Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer.

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            Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study.

            The goal of this study was to evaluate whether the addition of a purine analog, cladribine or fludarabine, to the standard induction regimen affects the outcome of adult patients with acute myeloid leukemia (AML). A cohort of 652 untreated AML patients with median age 47 years (range, 17 to 60 years) were randomly assigned to receive one of three induction regimens: DA (daunorubicin plus cytarabine), DAC (DA plus cladribine), or DAF (DA plus fludarabine). Postremission treatment was the same for all arms. Complete remission rate in the DAC arm was higher compared with the DA arm (67.5% v 56%; P = .01) as a consequence of reduced incidence of resistant disease (21% v 34%; P = .004). There was no significant difference in early outcome between the DAF and DA arms. The probability of overall survival was improved for the DAC arm (45% ± 4% at 3 years) compared with the DA arm (33% ± 4%; P = .02), and leukemia-free survival was comparable. Long-term outcome did not differ significantly for the comparison of the DAF and DA arms. A survival advantage of the DAC arm over the DA arm was observed among patients age 50 years or older (P = .005), those with initial leukocyte count above 50 × 10(9)/L (P = .03), and those with unfavorable karyotype (P = .03). DAF revealed a significant advantage over DA in patients with adverse karyotype (P = .02). The addition of cladribine to the standard induction regimen is associated with increased rate of complete remission and improved survival of adult patients with AML.
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              Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group.

              Patients with primary refractory AML and with early relapses have unfavorable prognoses and require innovative therapeutic approaches. Purine analogs fludarabine (FA) and cladribine (2-CdA) increase cytotoxic effect of Ara-C in leukemic blasts and inhibit DNA repair mechanisms; therefore its association with Ara-C and mitoxantrone (MIT) results in a synergistic effect. In the current report, we present the final results of multi-center phase II study evaluating the efficacy and toxicity of CLAG-M salvage regimen in poor risk refractory/relapsed AML patients. The induction chemotherapy consisted of 2-CdA 5 mg/m2, Ara-C 2 g/m2, MIT 10 mg/m2, and granulocyte-colony stimulating factor. In the case of PR, a second CLAG-M was administered. Patients in CR received consolidation courses based on high doses of Ara-C and MIT with or without 2-CdA. One hundred and eighteen patients from 11 centers were registered; 78 primary resistant and 40 relapsed. Sixty-six patients (58%) achieved CR after one or two courses of CLAG-M, 49 (35%) were refractory, and 8 (7%) died early. WBC >10 g/L and age >34 yr were factors associated with increased risk of treatment failure. Hematological toxicity was the most prominent toxicity of this regimen. The probability of OS at 4 yr was 14% (95% CI 4-23%). OS was influenced by age, WBC >10 g/L and poor karyotype in both univariate and multivariate analyses. The probability of 4 yr DFS was 30% for all 66 patients in CR (95% CI 11-49%). Poor karyotype was the only factor associated with decreased probability of DFS. We conclude that CLAG-M is a well-tolerated and highly effective salvage regimen in poor risk refractory/relapsed AML.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                29 May 2019
                : 13
                : 1867-1878
                [1 ]Department of Hematology, Zhongda Hospital Southeast University, Institute of Hematology Southeast University , Nanjing 210009, People’s Republic of China
                Author notes
                Correspondence: Zheng GeDepartment of Hematology, Zhongda Hospital Southeast University , Nanjing210009, Jiangsu Province, People’s Republic of ChinaTel +86 258 326 2468Fax +86 258 326 2471Email Janege879@ 123456hotmail.com
                © 2019 Zhou et al.

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                Page count
                Figures: 6, Tables: 1, References: 34, Pages: 12
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